1. Field of the Invention
The present invention relates to an aryloxy phenoxy acrylic compound having HIF-1 inhibition activity, a preparation method of the same, and a pharmaceutical composition containing the same as an active ingredient.
2. Description of the Related Art
Even after all the efforts over decades, cancer is still one of the most difficult untreatable diseases. Along with the striking advance in the fields of cancer cell biology, medicinal chemistry, etc, the development of a novel anticancer agent characteristically with a novel mechanism, such as Gleevec, has been made. Since Human Genome Project, novel target molecules has come to the front.
HIF-1 (Hypoxia Inducible Factor-1) is a transcription factor induced by hypoxia which is the heterodimer composed of HIF-1α subunit that is decomposed oxygen-dependently and HIF-1β subunit that is expressed all the time (Cancer Metastasis Rev., 17, 187-195, 1998; Trends Mol. Med., 7, 345-350, 2001). In the regular oxygen condition, the 402nd and the 564th proline residues of HIF-1α protein are hydroxylated, which are then combined with pVHL (Von Hippel-Lindau), the tumor suppressor gene, to be ubiquitinated that is later decomposed by proteasome. However, in hypoxia, a series of such reaction is inhibited, resulting in the accumulation of HIF-1α protein, which is combined with the existing HIF-1β protein. The conjugate migrates into the nucleus (Science 292, 468-472, 2001; Science 292, 468-472, 2001). The stability of HIF-1α is affected not only by oxygen partial pressure but also by other factors involved in oxygen sensing pathway which are exemplified by transition metal ions, iron chelators, and antioxidants, etc. HIF-1α can be accumulated regardless of oxygen concentration by the activation of such growth factors as epidermal growth factor, heregulin, insulin-like growth factors-I, and insulin-like growth factor-II, and oncogene such as ErβB2. When a growth factor is combined with each corresponding receptor, Pl3K-AKT, and MAPK signal transmission pathways are activated and HIF-1α protein synthesis is increased, resulting in the accumulation of HIF-1α protein.
HIF migrated into the nucleus is combined with HRE (Hypoxia Responsive Element, 5′-ACGTG-3′) on the promoter of the target gene to induce the gene expression. Those genes regulated by HIF identified up to date are at least 60 genes including vascular endothelial growth factor A (VEGF) (Nat. Rev. Cancer 2, 38-47, 2002; J. Biol. Chem. 278, 19575-19578, 2003; Nat, Med. 9, 677-684, 2003; Biochem. Pharmacol. 64, 993-998, 2002).
Hypoxia is a general symptom of cancer, particularly of solid tumor. Solid tumor cells are well adapted to hypoxic condition after being through various genetic changes, indicating the cancer cells are more aggravated and malignant with demonstrating resistance against anticancer agents. In fact, hypoxia has been known to be the major reason of malignancy of at least 70% of all kinds of tumors found in human (Nature 386, 403, 1997; Hockel M and Vaupel P, Semin. Oncol. 28, 36-41, 2001, Nature Med. 6, 1335, 2000; Bos et al. Cancer 2003, 97, 1573-1581). HIF-1 has been known to be a major molecule that regulates the adaptation of cancer cells to hypoxic condition. So, it can be said that the concentration of HIF-1α protein closely relates to the prognosis of cancer patients. The activation of HIF-1 by the growth factor, the activation of oncogene, or the inactivation of tumor suppressor gene such as pVHL induces the expressions of such genes as hexokinase 2, glucose transporter 1, erythropoietin, IGF-2, endoglin, VEGF, MMP-2, uPAR, and MDR1, in hypoxic condition, resulting in the increase of resistance against apoptosis, the increase of angiogenesis, the increase of cell proliferation, and the increase of cell invasion, and hence in the malignant alteration of cancer cells. Since HIF plays an important role in the growth, proliferation, and malignant alteration of solid tumor, research for the development of an anticancer agent has been focused on HIF (Cancer Res. 62, 4316, 2002; Nat Rev Drug Discovery 2, 1, 2003; Semenza et al. Nature Reviews Cancer 2003, 3, 721-732). The conventional anticancer agents such as taxol, rafamycin, and 17-AAG (17-allylaminogeldanamycin) and the drug in the middle of clinical test such as the low molecular compound YC-1 (3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole)), which is a guanylaly cyclase activator, are all HIF-1 inhibitors (Johnson et al Nature Reviews Drug Discovery 2003, 2, 1-9; Semenza et al. Nature Reviews Cancer 2003, 3, 721-732; JNCI 95, 516, 2003). Studies to develop a HIF-1 inhibitor with a novel structure is also actively undergoing with cell based reporter assay using HRE (Cancer Res 65, 4918, 2005; Cancer Cell 6, 33, 2004; Cancer Res. 62, 4316, 2002).
HIF-1 is useful as a target of cancer and also of other diseases whose worsen relates to the activation of angiogenesis. Hypoxia-induced HIF-1 activation activates angiogenesis related factors such as VEGF, which plays a certain role in the progress of not only cancer but also diabetic retinopathy or arthritis. Therefore, the compound inhibiting HIF-1 activated by hypoxia in the disease tissue can be effectively used as a novel therapeutic agent for such disease as diabetic retinopathy or rheumatoid arthritis (Eiji Ikeda, Pathology International, 2005, Vol 55, 603-610). However, this field is in a very nascent stage.
Thus, the present inventors have studied about compounds being able to inhibit HIF-1 activity, during which the inventors synthesized a compound inhibiting HIF-1 activity, suppressing angiogenesis and cancer metastasis, but having enhanced stability in human body, leading to the completion of this invention.